The Connective Tissue and Diseases Section began studying inflammatory myopathies (polymyositis, dermatomyositis, and related diseases) some years ago in an attempt to understand the relationship of autoantibodies to autoimmune disease. At the time, these diseases seemed to offer the best example of autoimmune diseases associated with highly specific disease-related autoantibodies and evidence of a viral etiology. They are very uncommon and hence relatively less studied than other autoimmune diseases, and they are very debilitating and hence in need of improved therapy. In order to attract patients here to allow more detailed clinical, immunological, genetic, and viral studies, we began doing trials of therapy and have completed a number of such studies. They are among the very few published controlled trials in this difficult to treat family of illnesses. These trials have encompassed a variety of approaches to immunosuppression. The most recent trial - a pilot trial of the anti-thyroid drug methimazole - was undertaken to make use of an unexpected property of the drug which was discovered by Dr. Leonard Kohn of NIDDK and Dr. Dinah Singer of NCI: that it can down-regulate MHC. This trial was completed in the past year. Patients with active myositis received a 6-month trial, with muscle biopsies being performed for research purposes at the beginning and three months into therapy. The level of mRNA of MHC Class I & II in muscle tissue and simultaneously-obtained peripheral blood monocytes was measured by Northern analysis. Patients were assessed carefully clinically, and the presence of inflammation in the quadriceps was measured by MRI. The MRI analysis employed a computer-based measure of tissue edema on the STIR image which was recently published by our group along with the Department of Radiology in the Journal of Magnetic Resonance Imaging. An attempt is being made, in collaboration with the laboratory of Eric Hoffman at Children's National Medical Center, to determine the effect of the drug on gene expression in affected muscle tissue. The clinical outcome of the trial, which closed at the end of the last fiscal year, has been analyzed by a new fellow, Dr. Imelda Cabalar, Dr. Jeanne Hicks of Rehabilitation Medicine, and Dr. Dee Koziol of the Clinical Center. Nineteen patients began the trial, of whom 16 had polymyositis. Although there were modest changes in muscle enzyme values (creatine kinase and aldolase) in a few patients, by the stringent but more clinically relevant criteria of muscle strength and ability to perform activities of daily living, none had improved in strength and only three in ADL at six months. A collaborating laboratory has not yet provided the quantitative changes in the levels of MHC I and II mRNA in paired muscle biopsies obtained from ten patients. These values will be critical in interpreting the potential of using regulation of MHC as a useful therapeutic avenue in this disease. In collaboration with the Alexion Corporation, we began a trial of a recombinant humanized antibody (H5g) directed at the late part of the pro-inflammatory complement pathway, anti-C5, in dermatomyositis. In that illness, activation of the late components of complement has been shown. The trial was double-blind, with a weekly infusion for two months. We were among five centers entering patients with dermatomyositis. Parallel trials were underway in several other diseases, including lupus and rheumatoid arthritis, when we began. We managed to enter three patients and have them complete the trial. At about the time of the completion of the third patient, the company informed us that a patient from another institution in one of the other trials had contracted meningococcal meningitis, an anticipated risk. We convened a committee of experts to decide how to respond. Meanwhile, the company provided its own set of recommendations. Our experts recommended a more conservative approach than the company did. The company would not adopt our recommendations, and our IRB, although it thought that our recommendations were adequate, would not let the trial continue because the company would not follow our more conservative approach. The clinical outcome of the trial is not currently known. We are in the late stages of planning a trial of one of the anti-TNF agents, infliximab, in myositis in collaboration with Dr. Fred Miller, a former member of my group in ARB who recently moved from the FDA to the intramural program of NIEHS, and Dr. Lisa Rider. Dr. Rider has continued to lead a collaborative group of pediatric rheumatologists throughout the country and in Canada in a thorough clinical and laboratory description of pediatric myositis. We have begun a collaboration with Dr. Eric Hoffman of Children's National Medical Center to examine the possible role of abnormalities in muscle structural proteins in determining the response to therapy in myositis. This is particularly intended to uncover patients with genetic abnormalities of muscle masquerading as myositis. This promises to be a fruitful approach. So far, with the aid of Dr. Hoffman and Dr. Kondi Wong of the Armed Forces Institute of Pathology, we have found two patients who have been long treated for myositis who have genetic diseases of muscle structural proteins and another who may have both myositis and an abnormality of a structural protein. These studies employ both standard immunologic techniques and microarray expression analysis.